Oral Administration of Collagen Hydrolysates Improves Glucose Tolerance in Normal Mice Through GLP-1-Dependent and GLP-1-Independent Mechanisms.

The aim of this study was to evaluate the antidiabetic properties of collagen hydrolysates (CHs). CHs exhibited dipeptidyl peptidase-IV inhibitory activity and stimulated glucagon-like-peptide-1 (GLP-1) secretion in vitro. We also determined whether CHs improve glucose tolerance in normal mice. Oral administration of CHs suppressed the glycemic response during the oral and intraperitoneal glucose tolerance tests (OGTT and IPGTT), but the effects were weaker in IPGTT than in OGTT. CHs had no effect on the gastric emptying rate. A pretreatment with the GLP-1 receptor antagonist, exendin 9-39 (Ex9), partially reversed the glucose-lowering effects of CHs, but only when coadministered with glucose. CHs administered 45 min before the glucose load potentiated the glucose-stimulated insulin secretion. This potentiating effect on insulin secretion was not reversed by the pretreatment with Ex9, it appeared to be enhanced. These results suggest that CHs improve glucose tolerance by inhibiting intestinal glucose uptake and enhancing insulin secretion, and also demonstrated that GLP-1 was partially involved in the inhibition of glucose uptake, but not essential for the enhancement of insulin secretion.

Inhibitors of Plasmodium falciparum methionine aminopeptidase 1b possess antimalarial activity.

With >1 million deaths annually, mostly among children in sub-Saharan Africa, malaria poses one of the most critical challenges in medicine today. Although introduction of the artemisinin class of antimalarial drugs has offered a temporary solution to the problem of drug resistance, new antimalarial drugs are needed to ensure effective control of the disease in the future. Herein, we have investigated members of the methionine aminopeptidase family as potential antimalarial targets. The Plasmodium falciparum methionine aminopeptidase 1b (PfMetAP1b), one of four MetAP proteins encoded in the P. falciparum genome, was cloned, overexpressed, purified, and used to screen a 175,000-compound library for inhibitors. A family of structurally related inhibitors containing a 2-(2-pyridinyl)-pyrimidine core was identified. Structure/activity studies led to the identification of a potent PfMetAP1b inhibitor, XC11, with an IC(50) of 112 nM. XC11 was highly selective for PfMetAP1b and did not exhibit significant cytotoxicity against primary human fibroblasts. Most importantly, XC11 inhibited the proliferation of P. falciparum strains 3D7 [chloroquine (CQ)-sensitive] and Dd2 (multidrug-resistant) in vitro and is active in mouse malaria models for both CQ-sensitive and CQ-resistant strains. These results suggest that PfMetAP1b is a promising target and XC11 is an important lead compound for the development of novel antimalarial drugs.